Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof

Abstract

Provided herein is a bridged bring compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating treat hepatitis C virus C(HCV) infection or hepatitis C disease. Furthermore provided herein are pharmaceutical compositions containing the compounds and the method of using the compounds or pharmaceutical compositions thereof in the treatment of HCV infection or hepatitis C.

What is claimed is: 
     
       1. A compound having Formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein X 3  is (CR 7 R 7a ) e ; 
         each R 7  and R 7a  is independently H or C 1-3  alkyl; 
         e is 1 or 2; 
         each of A and A′ is independently 
       
       
         
           
           
               
               
           
         
         R 1  is C 1-4  alkyl, C 1-4  heteroalkyl or C 6-10  aryl; 
         R 2  is H, deuterium, C 1-4  alkyl, C 1-4  heteroalkyl or C 6-10  aryl; 
         R 3  and R 4 , together with N—CH to which they are attached, form one of the following groups: 
       
       
         
           
           
               
               
           
         
         wherein each R 15  is independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, oxo(═O), phenyl, C 1-4  alkyl, C 1-4  hydroxyalkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkoxy-C 1-4 -alkyl, C 1-4  alkylamino, C 6-10  arylamino, C 6-10  aryloxy, C 1-9  heteroaryl, C 1-9  heteroaryloxy, C 2-6  alkenyl or C 2-10  heterocyclyl; 
         each R 6  is independently H, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, C 1-4  amnioalkyl, C 1-6  alkoxy-C 1-4 -alkyl, C 1-6  alkylamino-C 1-4 -alkyl, C 6-10  aryl-C 1-4 -alkyl, C 6-10  aryl, C 2-10  heterocyclyl or C 3-8  cycloalkyl; 
         each n 1  and n 2  is independently 1, 2, 3 or 4; 
         each R 5a  and R 6a  is independently H, deuterium, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, mercapto, nitro, C 1-6  alkoxy, C 1-6  alkyl, C 6-10  aryl, —CF 3 , C 1-6  alkylamino, C 3-10  cycloalkyl or C 6-10  aryloxy; 
         each R 9  and R 9a  is independently H, deuterium, C 1-6  alkyl, C 1-6  alkoxy-C 1-6 -alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  heteroalkyl, C 1-6  alkylamino-C 1-6 -alkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C C 2-10  heterocyclyl-C 1-6 -alkyl, C 3-8  cycloalkyl-C 1-6 -alkyl, C 6-10  aryl, C 1-9  heteroaryl, C 2-10  heterocyclyl or C 3-8  carbocyclyl; 
         each of R 8  and R 8a  is independently H, deuterium, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  heteroalkyl, C 6-10  aryl, C 2-10  heterocyclyl, C 3-8  cycloalkyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 2-10  heterocyclyl-C 1-6 -alkyl or C 3-8  cycloalkyl-C 1-6 -alkyl; and 
         f is 0, 1, 2, 3 or 4. 
       
     
     
       2. The compound according to  claim 1 , wherein
 X 3  is (CR 7 R 7a ) e ; 
 e is 1 or 2; and 
 each R 7  and R 7a  is independently H. 
 
     
     
       3. The compound according to  claim 1 , wherein R 3  and R 4 , together with N—CH to which they are attached, form one of the following groups: 
       
         
           
           
               
               
           
         
         wherein each R 15  is independently H, F, Cl, Br, I, cyano, hydroxy, phenyl, C 1-4  alkyl, C 1-4  hydroxyalkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkoxy-C 1-4 -alkyl, or C 2-10  heterocyclyl; 
         and 
         each n 1  and n 2  is independently 1, 2, 3 or 4. 
       
     
     
       4. The compound according to  claim 1  having formula (II): 
       
         
           
           
               
               
           
         
         wherein each of A and A′ is independently 
       
       
         
           
           
               
               
           
         
         R 1  is methyl, ethyl, i-propyl, or phenyl; 
         R 2  is H, deuterium, methyl, ethyl, i-propyl, or phenyl; 
         each R 5a  is independently H, deuterium, oxo (═O), —CF 3 , methyl, ethyl, phenyl, benzyl, F, Cl, Br or I; 
         each R 6a  is independently H, deuterium, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, i-propyl, cyclohexyl, phenyl, benzyl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-3  alkylamino or C 3-8  cycloalkyl; 
         each of R 8  and R 8a  is independently H, deuterium, methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, i-propyl or t-butyl; 
         each of R 9  and R 9a  is independently H, deuterium, methyl, ethyl, 1-methylpropyl, phenyl, i-propyl, tetrahydropyranyl, or t-butyl; 
         each R 15  is independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, methoxylmethyl, i-propyl, i-butyl or phenyl; 
         n 1  is 1, 2, 3 or 4; and 
         f is 0, 1, 2, 3 or 4. 
       
     
     
       5. The compound according to  claim 1  having one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. 
     
     
       6. A pharmaceutical composition comprising the compound according to  claim 1 ; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 
     
     
       7. The pharmaceutical composition according to  claim 6  further comprising an anti-HCV agent; wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, a HCV neutralizing polyclonal antibody (CIVACIR®), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA-975, ombitasvir, EDP-239, PPI-668, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, BI-2013335, ciluprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055, MK-3682, GS-9669, odalasvir, furaprevir, setrobuvir, alisporivir, BIT-225, AV-4025, ACH-3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD-6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125 or a combination thereof; and wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof. 
     
     
       8. A method of inhibiting hepatitis C virus (HCV) replication comprising administering the compound according to  claim 1 . 
     
     
       9. A method of treating hepatitis C virus (HCV) infection or disorder in a patient in need of a treatment for HCV infection or disorder, wherein the method comprises administering a therapeutically effective amount of the compound according to  claim 1  to the patient. 
     
     
       10. A method of inhibiting hepatitis C virus (HCV) replication comprising administering the pharmaceutical composition according  claim 6 . 
     
     
       11. A method of treating hepatitis C virus (HCV) infection or disorder in a patient in need of a treatment for HCV infection or disorder, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition according  claim 6  to the patient.